Submissions for variant NM_000088.4(COL1A1):c.3277C>T (p.Arg1093Cys)

gnomAD frequency: 0.00002  dbSNP: rs72656307

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631466	SCV000752546	uncertain significance	Osteogenesis imperfecta type I	2024-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1093 of the COL1A1 protein (p.Arg1093Cys). This variant is present in population databases (rs72656307, gnomAD 0.01%). This missense change has been observed in individual(s) with multiple arterial dissections and osteopenia with wrist fractures (PMID: 17211858). ClinVar contains an entry for this variant (Variation ID: 161457). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL1A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects COL1A1 function (PMID: 17211858). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001753528	SCV001986032	uncertain significance	not provided	2020-07-14	criteria provided, single submitter	clinical testing	Has been reported in an individual with aortic dissection and aneurysms, but without other features of EDS (Malfait et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Located in the Gly-Xaa-Yaa triple helical region of the pro-alpha1(I) chain encoded by the COL1A1 gene, where triplet glycine substitutions are the most common cause of osteogenesis imperfecta (OI). The effect of missense substitution at the X and Y positions are more difficult to predict; however, multiple variants that result in introduction of a Cys residue in pro-alpha1(I) have been reported to be pathogenic (Dalgleish, 1998).; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 161457; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 17211858, 28306225)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277297	SCV002565516	uncertain significance	Ehlers-Danlos syndrome	2018-10-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288660	SCV002580206	uncertain significance	Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1	2021-09-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492548	SCV002783739	uncertain significance	Osteogenesis imperfecta with normal sclerae, dominant form; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Infantile cortical hyperostosis; Ehlers-Danlos syndrome, arthrochalasia type; Osteogenesis imperfecta type I; Osteoporosis; Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1	2022-01-14	criteria provided, single submitter	clinical testing
Science for Life laboratory, Karolinska Institutet	RCV000148991	SCV000088633	unknown	Malignant tumor of prostate		no assertion criteria provided	not provided	Converted during submission to Uncertain significance.